Interleukin 1 (IL-1) is a protein cytokine produced primarily by cells of the macrophage/monocyte lineage. There are two distinct IL-1 genes capable of encoding IL-1 polypeptides--IL-1.alpha. and IL-1.beta. [P- Auron et al., "Nucleotide Sequence Of Human Monocyte Interleukin-1 Precursor cDNA", Proc. Natl. Acad. Sci., USA, 81, p. 7907 (1984); C. March et al., "Cloning, Sequences And Expression Of Two Distinct Human Interleukin 1 Complementary DNA's .alpha. and .beta.," Nature, 315, p. 641 (1985)]. Studies of their respective biological activities using recombinant IL-1.alpha. and .beta. have indicated thus far that both forms of IL-1 share multiple biological activities.
IL-1 has several distinct biological activities. One of these activities--lymphocyte-activating factor (LAF) activity--results in IL-1 being an immunological response mediator and as such, IL-1 stimulates the maturation, differentiation and growth of many cell types, such as immature T and B lymphocytes [P. Auron et al., Proc. Natl. Acad. Sci. USA, 81, supra]. Another of IL-1's activities--mononuclear cell factor (MCF) activity--results in IL-1 playing a central role in the regulation of diverse inflammatory responses [C. Dinarello, "An Update of Human Interleukin 1", J. Clin. Immun., 5, p. 287 (1985)] and, as such, IL-1 stimulates several cells, e.g., fibroblasts and chondrocytes, to produce prostaglandin E.sub.2 (PGE.sub.2) and collagenase, respectively. These responses are involved in the pathogenesis of such joint diseases as rheumatoid arthritis or diseases associated with the destruction of tissue [J. Dayer, "Cytokines and Other Mediators in Rheumatoid Arthritis", Springer Semin. Immunopath, 7, p. 387 (1984)]. Further, IL-1 is known to induce the production of IL-2 [J. W. Lowenthal et al. "IL-1 Dependent Induction Of Both IL-2 Secretion and IL-2 Receptor Expression By Thymoma Cells", J. Imm., 137, pp. 1226-1231 (1986)]which is involved in T-cell proliferation. Finally, IL-1 is also known to stimulate molecules on endothelial cells to trap white blood cells [J. Oppenheimet al., "There is More Than One Interleukin 1", Immun. Today, 7, p. 45 (1986) ].
It would therefore be of interest to identify and isolate an IL-1 inhibitor which suppresses antigen specific T-cell and B-cell proliferation and suppresses prostaglandin and collagenase synthesis by fibroblasts. Such a compound would be useful for the treatment of disorders involving immune and inflammatory responses. Still further, it would be desirable to isolate an Il-1 inhibitor capable of suppressing IL-1 mediated IL-2 production. It is of further interest to identify a compound that selectively inhibits the activities of IL-1 without concommitantly inhibiting other proteins, e.g., tumor necrosis factors, such as TNF-.alpha., that share several biological properties of IL-1, i.e., PGE.sub.2 and collagenase production by human derreal fibroblasts [J. Dayer et al., "Cachectin/Tumor Necrosis Factor Stimulates Collogenase and Prostaglandin E.sub.2 Production by Human Synovial Cells and Dermal Fibroblasts", J. Exp. Med., 162, p. 2163 (1985)]or induction of fibroblast proliferation [P. Seckinger et al., "A Urine Inhibitor of Interleukin 1 Activity Affects Both Interleukin 1 .alpha. And .beta. But Not Tumor Necrosis Factor .alpha.", J. Immun. 139, p. 1541 (1987)].
At present, compounds reported as displaying inhibitory effects on IL-1, such as prostaglandins, act primarily as nonselective inhibitors. It has also been reported that urine of febrile patients contains a 20-30 kD selective inhibitor of IL-1 [Z. Liao et al. "Identification Of a Specific Interleukin 1 Inhibitor In The Urine Of Febrile Patients", J. Exp. Med., 159, p. 126 (1984) ]. Liao does not suggest that this compound is other than in very crude form or that it inhibits the MCF activity of IL-1, inhibits the binding of IL-1 to target cell receptors, or inhibits fibroblast proliferation in the presence of IL-1. A second compound reported to have IL-1 inhibitory effects [W. Arend et al., "Effects of Immune Complexes On Production By Human Monocyrtes of Interleukin or an Interleukin 1 Inhibitor", J. Immun., 134, p. 3868 (1985)]is produced by human monocytes cultured on adherent immune complexes. However, the Arend report is ambiguous with respect to whether the compound inhibits both the LAF and MCF activity of IL-1 (see page 3874). In any event, the Arend article does not report that the compound is substantially pure or that it blocks IL-1 binding to target cell receptors or inhibits fibroblast proliferation in the presence of IL-1. A third compound reported to have IL-1 inhibitory effects [J-F. Balavoine et al., "Prostaglandin E.sub.2 .And Collagenase Production By Fibroblasts And Synovial Cells Is Regulated By Urine-derived Human Interleukin 1 And Inhibitor(s)", J. Clin. Invest. 78, p. 1120 (1986)]is suggested to be in very crude form and its mode of action is not described.